Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antibodies (Abs) hydrolyzing proteins, DNA, and RNA are detected in the blood of patients with various autoimmune diseases. In the present work, homogeneous preparations of IgG Abs from the blood of the healthy donors as well as patients with A, B, C, and delta types of viral hepatitis, influenza, pneumonia, tuberculosis, tonsillitis, duodenal ulcer, and some types of cancer were purified. For the first time, the fraction of IgG and its Fab fragments of patients with viral hepatitis were shown to have high DNA- and RNA-hydrolyzing activity. In case of Abs from the healthy donors and patients with other diseases, high activity of Abs was not detected. The data obtained by various methods indicate that the activity of hepatitis Abs is an intrinsic property of the immunoglobulins. The relative rates of hydrolysis of cCMP, poly(U), poly(A), poly(C), and tRNA(Phe) by hepatitis Abs were compared with those of RNase A and other RNases from human blood. Significant differences in activities of Abs and nucleases in hydrolysis of model substrates were demonstrated. Thus, catalytically active Abs can appear in the blood of patients not only with autoimmune disorders, but with viral diseases as well.
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PMID:DNA- and RNA-hydrolyzing antibodies from the blood of patients with various forms of viral hepatitis. 948 69

In order to evaluate uranyl photocleavage as a tool to identify and characterize structural and dynamic properties in RNA, we compared uranyl cleavage sites in five RNA molecules with known X-ray structures, namely the hammerhead and hepatitis delta virus ribozymes, the P4-P6 domain of the Tetrahymena group I intron, as well as tRNA(Phe) and tRNA(Asp) from yeast. Uranyl photocleavage was observed at specific positions in all molecules investigated. In order to characterize the sites, photocleavage was performed in the absence and in increasing amounts of MgCl(2). Uranyl photocleavage correlates well with sites of low calculated accessibility, suggesting that uranyl ions bind in tight RNA pockets formed by close approach of phosphate groups. RNA foldings require ion binding, usually magnesium ions. Thus, upon the adoption of the native structure, uranyl ions can no longer bind well except in flexible and open to the solvent regions that can undergo induced-fit without disrupting the native fold. Uranyl photocleavage was compared to N-ethyl-N-nitrosourea and lead-induced cleavages in the context of the three-dimensional X-ray structures. Overall, the regions protected from ENU attack are sites of uranyl cleavage, indicating sites of low accessibility which can form ion binding sites. On the contrary, lead cleavages occur at flexible and accessible sites and correlate with the unspecific cleavages prevalent in dynamic and open regions. Applied in a magnesium-dependent manner, and only in combination with other backbone probing agents such as N-ethyl-N-nitrosourea, lead and Fenton cleavage, uranyl probing has the potential to reveal high-affinity metal ion environments, as well as regions involved in conformational transitions.
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PMID:Evaluation of uranyl photocleavage as a probe to monitor ion binding and flexibility in RNAs. 1087 69

Sialodacryoadenitis virus (SDAV) is a coronavirus that is commonly found in laboratory rats and that causes sialodacryoadenitis and respiratory illness. We cloned and sequenced the 3' terminal 9.8 kb of the genomic RNA and analyzed the structure of the viral genome. As with mouse hepatitis coronaviruses (MHVs), the SDAV genome was able to code for a spike protein, a small membrane protein, a membrane-associated protein, and a nucleocapsid protein. In addition, the hemagglutinin-esterase gene capable of encoding a protein of 439 amino acids (aa) was identified. The putative functional site for acetylesterase activity was present in the HE protein as Phe-Gly-Asp-Ser (FGDS), suggesting that the SDAV HE protein might have retained the esterase activity. Immediately upstream of the HE gene and downstream of the polymerase 1b gene, the NS2 nonstructural-protein gene was identified with a coding capacity of 274 aa. A motif of UCUAAAC was identified as a potential transcription signal for subgenomic mRNA synthesis. Large insertions of 172, 127, and 44 aa were detected in the N-terminal half of the predicted S protein of SDAV when its sequence was compared to the sequences of MHV 2, MHV JHM, and MHV A59, respectively. The sequence information on the SDAV S-protein gene was applied to a differential diagnostic PCR to detect and distinguish the rat coronavirus from mouse coronaviruses. This is the first report on the comprehensive genetic information of any rat coronavirus.
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PMID:Primary structure of the sialodacryoadenitis virus genome: sequence of the structural-protein region and its application for differential diagnosis. 1088 53

Alpha1-antitrypsin (alpha1AT) deficiency is an autosomal recessive disorder that can cause pulmonary emphysema and liver disease. We report here the case of a 59-year-old woman who was admitted to hospital for evaluation of jaundice. She had no history of hepatitis or childhood liver disease. She had never received a blood transfusion, nor had she abused drugs or alcohol. Transjugular liver biopsy was then performed and revealed a micronodular cirrhosis. Ten months later, because of persistent liver cell failure and ascites, she underwent an orthotopic liver transplantation. Investigation of alpha1AT system in the proband revealed a substantial decrease in serum alpha1AT associated with a low elastase inhibitory capacity. The Pi phenotype revealed a PiM-like profile. Sequencing of exons 1-5 demonstrated the presence of the M3 allele. Moreover, a triple nucleotide deletion was detected in exon 2 of one allele. This caused an "in-phase" frameshift, coding for a protein deficient in a single Phe residue, which corresponded to the Mmalton variant. After liver biopsy, periodic acid-Schiff-positive acidophilic bodies resistant to diastase digestion were observed in the cytoplasm of hepatocytes. These results demonstrated that our patient had a heterozygous M3Mmalton alpha1AT genotype related to a deficiency phenotype. This observation is the first of a patient with heterozygous Mmalton genotype associated with an alpha1AT deficiency that induced severe liver disease requiring orthotopic liver transplantation.
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PMID:Heterozygous M3Mmalton alpha1-antitrypsin deficiency associated with end-stage liver disease: case report and review. 1146 49

Five patients of cholestatic jaundice and multiple hyperaminoacidemias were uncovered during neonatal mass screening for homocystinuria. All five patients had increased plasma levels of methionine, citrulline, tyrosine, threonine, phenylalanine, lysine and arginine. Compared with those of age-matched cholestatic disease controls, idiopathic neonatal hepatitis (n=9) and biliary atresia (n=14), plasma levels of three amino acids, citrulline, methionine, and threonine, were significantly greater, respectively (P<0.01). Liver biopsies examined in four patients uniformly showed diffuse hepatic fatty liver with micro- and macrovesicular droplets without giant cell transformation. Administration of fat-soluble vitamins and formula milk containing middle-chain triglyceride resulted in normalization of amino acid profiles by 6 weeks after the treatment. All liver function tests normalized by 17 months of age.
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PMID:An undescribed subset of neonatal intrahepatic cholestasis associated with multiple hyperaminoacidemia. 1147 Jun 24

The soluble receptor-resistant (srr) mutants, srr7 and srr11, isolated from a murine coronavirus, mouse hepatitis virus (MHV) JHMV, have an amino acid mutation at positions 1114 (Leu to Phe) and 65 (Leu to His), respectively, in the spike (S) protein. These mutants failed to efficiently infect BHK cells expressing CEACAM1b (BHK-R2), due to their low entry into this cell line, although they infected cells expressing CEACAM1a (BHK-R1) in a manner similar to that of wild-type (wt) JHMV cl-2 (Matsuyama and Taguchi, Virology 273, 80-89, 2000). Following the repeated passage of these mutants through BHK-R2 cells, viruses were no longer isolated from srr11-infected cells, while two distinct mutants, srr7A and srr7B, were obtained from srr7-infected cells. Srr7A and srr7B grew 2 log10 higher than srr7 and induced fusion in BHK-R2 cells, being similar to wt virus. In addition to the amino acid change at position 1114 that stemmed from parental srr7, srr7A and srr7B had mutations around position 280, corresponding to the third region of the S1N330 receptor-binding site (S1N330-III) common to all MHV strains examined thus far. Srr7A and srr7B S proteins showed high fusogenicity in both BHK-R1 and BHK-R2 cells, like the wt virus, while srr7Aa and srr7Ba S proteins, which had mutations in S1N330-III but not at amino acid 1114, exhibited profoundly reduced fusion activity in these cell lines. These findings suggest that communication between S1N330-III and the amino acid at position 1114 is important for efficient fusion activity in BHK-R2 cells. S1N330-III is a possible region in the S1 involved in viral entry into cells.
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PMID:Communication between S1N330 and a region in S2 of murine coronavirus spike protein is important for virus entry into cells expressing CEACAM1b receptor. 1203 74

Autoantibodies to the ribosomal phospho (-P) proteins P0, P1, and P2, collectively referred to as Rib-P, are specifically found in 10-40% of patients with systemic lupus erythematosus (SLE). These antibodies are believed to be correlated with lupus nephritis, hepatitis, and central nervous system involvement. The major immunoreactive epitope of these ribosomal antigens has been localized to the carboxy terminus, which is a highly conserved domain of all three proteins and contains two phosphorylated serine residues. The phosphorylated amino acids of the P proteins are known not to be critical epitope determinants. Furthermore, epitope-mapping studies have shown that the major epitope is located within the last 11 C-terminal amino acids. Using peptide arrays we identified more precisely this shared epitope as the six C-terminal amino acids GFGLFD and elucidated the molecular recognition events of anti-Rib-P antibodies at the amino acid level. We identified Phe(111) and Phe(114) of Rib-P2 as the key residues for the interaction, with further contributions of Gly-112 and Asp-115. This amino acid stretch is also present in proteins of several pathogenic micro-organisms such as Trypanosoma cruzi, Brugia malayi, Pseudomonas aeruginosa, Candida albicans, several Leishmania species, and Bartonella henselae. Using newly developed ELISA systems with a C-terminal peptide (C22) and the recombinant proteins (P0, P1, and P2) as antigens we found a high specificity of anti-Rib-P antibodies for SLE and demonstrated positive correlations with anti-U1-C, anti-Sm-B/B' and anti-D and anti-dsDNA antibodies. The sensitivity and specificity in the peptide (C22) based assay varied between 12.8%/100% and 23.4%/96.7% for SLE, depending on the assigned cutoff. In contrast to other studies, we found no significant correlation of anti-Rib-P reactivity with central nervous system manifestations or renal involvement in SLE patients. We conclude that the epitope motif GFGLFD in the C-termini of the ribosomal P proteins is the key determinant of anti-Rib-P antibodies, and that the C22 peptide and the recombinant proteins can be used equally well for the detection of anti-Rib-P antibodies. The role of the major Rib-P epitope in the development of anti-ribosomal P antibodies and in the pathogenesis of SLE remains a subject of further investigation.
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PMID:Characterization of the human autoimmune response to the major C-terminal epitope of the ribosomal P proteins. 1268 28

Conformational diseases are caused by a structural rearrangement within a protein that results in aberrant intermolecular linkage and tissue deposition. This is typified by the polymers that form with the Z deficiency variant of alpha 1-antitrypsin (Glu-342 --> Lys). These polymers are retained within hepatocytes to form inclusions that are associated with hepatitis, cirrhosis, and hepatocellular carcinoma. We have assessed a surface hydrophobic cavity in alpha1-antitrypsin as a potential target for rational drug design in order to prevent polymer formation and the associated liver disease. The introduction of either Thr-114 --> Phe or Gly-117 --> Phe on strand 2 of beta-sheet A within this cavity significantly raised the melting temperature and retarded polymer formation. Conversely, Leu-100 --> Phe on helix D accelerated polymer formation, but this effect was abrogated by the addition of Thr-114 --> Phe. None of these mutations affected the inhibitory activity of alpha 1-antitrypsin. The importance of these observations was underscored by the finding that the Thr-114 --> Phe mutation reduced polymer formation and increased the secretion of Z alpha 1-antitrypsin from a Xenopus oocyte expression system. Moreover cysteine mutants within the hydrophobic pocket were able to bind a range of fluorophores illustrating the accessibility of the cavity to external agents. These results demonstrate the importance of this cavity as a site for drug design to ameliorate polymerization and prevent the associated conformational disease.
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PMID:Targeting a surface cavity of alpha 1-antitrypsin to prevent conformational disease. 1280 89

Glutathione transferase zeta (GSTZ1-1) is the major enzyme that catalyzes the metabolism of alpha-halo acids such as dichloroacetic acid, a carcinogenic contaminant of chlorinated water. GSTZ1-1 is identical with maleylacetoacetate isomerase, which catalyzes the penultimate step in the catabolic pathways for phenylalanine and tyrosine. In this study we have deleted the Gstz1 gene in BALB/c mice and characterized their phenotype. Gstz1(-/-) mice do not have demonstrable activity with maleylacetone and alpha-halo acid substrates, and other GSTs do not compensate for the loss of this enzyme. When fed a standard diet, the GSTZ1-1-deficient mice showed enlarged liver and kidneys as well as splenic atrophy. Light and electron microscopic examination revealed multifocal hepatitis and ultrastructural changes in the kidney. The addition of 3% (w/v) phenylalanine to the drinking water was lethal for young mice (<28 days old) and caused liver necrosis, macrovesicular steatosis, splenic atrophy, and a significant loss of circulating leukocytes in older surviving mice. GSTZ1-1-deficient mice showed constitutive induction of alpha, mu, and pi class GSTs as well as NAD(P)H:quinone oxidoreductase 1. The overall response is consistent with the chronic accumulation of a toxic metabolite(s). We detected the accumulation of succinylacetone in the serum of deficient mice but cannot exclude the possibility that maleylacetoacetate and maleylacetone may also accumulate.
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PMID:Mice deficient in glutathione transferase zeta/maleylacetoacetate isomerase exhibit a range of pathological changes and elevated expression of alpha, mu, and pi class glutathione transferases. 1527 41

The identification of the epitopes recognized by autoantibodies against cytochrome P450s (CYPs) associated with drug-induced hepatotoxicity is difficult because of their conformational nature. In the present investigation, we used a novel approach based on the analysis of the whole molecule antigenic capacity following single amino acid substitutions to identify the conformational epitopes on CYP2E1. A molecular model of CYP2E1 was generated based on the CYP2C5 crystal structure, and potential motifs for amino acid exchanges were selected by computer simulation in the surface of alpha helices and beta sheets. Fourteen modified, apparently correctly folded CYP2E1 variants were produced in Escherichia coli and evaluated in immunoprecipitation experiments using sera with anti-CYP2E1 autoreactivity from 10 patients with halothane hepatitis and 12 patients with alcoholic liver disease. Ala substitution of Glu-248 and Lys-251 as well as of Lys-324, Lys-342, Lys-420, and Phe-421 severely decreased or abolished CYP2E1 recognition by the majority of both the halothane hepatitis and alcoholic liver disease sera, whereas the other substitutions had only minor effects. Based on the structural model, these substitutions identified two distinct epitopes on the CYP2E1 surface corresponding to the G-helix and an area formed by juxtaposition of the J' and K'' helices, respectively. The combined use of molecular modeling and single amino acid mutagenesis is thus a useful approach for the characterization of conformational epitopes recognized by autoantibodies.
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PMID:Use of molecular simulation for mapping conformational CYP2E1 epitopes. 1545 90


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